|Número de publicación||US7604984 B2|
|Tipo de publicación||Concesión|
|Número de solicitud||US 11/027,547|
|Fecha de publicación||20 Oct 2009|
|Fecha de prioridad||29 Dic 2004|
|También publicado como||US20060141611, US20060205058, WO2006071992A1|
|Número de publicación||027547, 11027547, US 7604984 B2, US 7604984B2, US-B2-7604984, US7604984 B2, US7604984B2|
|Inventores||Anthony G. Frutos, Jacques Gollier, Jinlin Peng, Garrett A. Piech, Michael B. Webb|
|Cesionario original||Corning Incorporated|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citas de patentes (58), Otras citas (17), Citada por (5), Clasificaciones (28), Eventos legales (3)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
This application is related to U.S. patent application Ser. No. 11/027,509 filed concurrently herewith and entitled “Method for Creating a Reference Region and a Sample Region on a Biosensor and the Resulting Biosensor” the contents of which are hereby incorporated by reference herein.
1. Field of the Invention
The present invention relates to an optical reader system that uses a scanned optical beam to interrogate one or more biosensors. In one embodiment, the biosensors are incorporated within the wells of a microplate.
2. Description of Related Art
Manufacturers of optical reader systems are always trying to design a new and improved optical reader system that can be used to interrogate a resonant waveguide grating biosensor to determine if a biomolecular binding event (e.g., binding of a drug to a protein) occurred on a surface of the biosensor. One such new and improved optical reader system is the subject of the present invention.
The present invention includes an optical reader system that uses a scanned optical beam to interrogate a resonant waveguide grating biosensor to determine if a biomolecular binding event occurred on a surface of the biosensor. In one embodiment, the optical reader system includes a light source, a detector and a processor (e.g., computer, DSP). The light source outputs an optical beam which is scanned across a moving biosensor and while this is happening the detector collects the optical beam which is reflected from the biosensor. The computer processes the collected optical beam and records the resulting raw spectral or angle data which is a function of a position (and possibly time) on the biosensor. The processor can then analyze the raw data to create a spatial map of resonant wavelength (peak position) or resonant angle which indicates whether or not a biomolecular binding event occurred on the biosensor. Several other uses of the raw data are also described herein.
A more complete understanding of the present invention may be had by reference to the following detailed description when taken in conjunction with the accompanying drawings wherein:
In other aspects of the present invention, the computer 110 can analyze the raw spectral data 114 to perform a wide range of tasks in addition to detecting a biomolecular binding event on the biosensor 102. For instance, the processor 110 can analyze the raw spectral data 114 to create a spatial map of reflected power that can be used to locate an edge of a grating in the biosensor 102 so that biosensor 102 can be properly re-located after being removed and reinserted into a path of the optical beam 104. And, the processor 110 can analyze the raw spectral data 114 to create a spatial map of reflected power and reflected wavelength which can be used to evaluate the locations, quantities and sizes of defects on the biosensor 102. Moreover, the processor 110 can analyze the raw spectral data 114 to create a spatial map of reflected wavelength data that can be used to ameliorate undesirable effects on changes in measured wavelengths that arise from drifts of the detector 108 and other sources of error including waveguide coating drift, source spectra variations overtime, or bulk index error. More details about the optical reader system 100 and the uses of the raw spectral data 114 are described below after a brief description is provided about the structure of the biosensor 102 and about the different ways the biosensor 102 can be used to detect a biomolecular binding event.
As shown in
The biosensor 102 makes use of changes in the refractive index at the sensor surface that affect the waveguide coupling properties of the optical beam 104 emitted from the light source 106 and the optical beam 112 reflected back into the detector 108 to enable label-free detection of a biological substance 124 (e.g., cell, molecule, protein, drug, chemical compound, nucleic acid, peptide, carbohydrate) on the superstrate 103 (sensing region) of the biosensor 102. The biological substance 124 may be located within a bulk fluid that is deposited on the superstrate 103 (sensing region) of the biosensor 102 and it is the presence of this biological substance 124 that alters the index of refraction at the surface 126 of the biosensor 102. Thus, to detect the biological substance 124, the biosensor 102 needs to be at least probed with an optical beam 104 and then a reflected optical beam 112 received at the detector 108 is analyzed to determine if there are any changes (˜1 part per million) in the refractive index caused by the presence of the biological substance 124. In one embodiment, the top surface 126 may be coated with biochemical compounds (not shown) that only allow surface attachment of specific complementary biological substances 124 which enables a biosensor 102 to be created that is both highly sensitive and highly specific. In this way, the optical reader system 100 and biosensor 102 may be used to detect a wide variety of biological substances 124. And, if multiple biosensors 102 are arranged in array an like in a microplate then they may be used to enable high throughput drug or chemical screening studies (see
The sensitivity of the biosensor 102 may be best understood by analyzing the structure of the diffraction grating 120 and the waveguide 122. The optical beam 104 shone on the diffraction grating 120 can only be coupled into the waveguide 122 if its wave vector satisfies the following resonant condition as shown in equation no. 1:
k x ′=k x−κ 
where kx′ is the x-component of the incident wave vector, kx is the guided mode wave vector, and κ is the grating vector. The grating vector κ is defined as a vector having a direction perpendicular to the lines of the diffraction grating 120 and a magnitude given by 2π/Λ where Λ is the grating period (pitch) (see
Where θ is the angle of incidence of the optical beam 104, ninc is the index of refraction of the incident medium, λ is the wavelength of the optical beam 104, and neff is the effective index of refraction of the waveguide 122. The effective index of the waveguide 122 is a weighted average of the indices of refraction that the optical waveguide mode field “sees” as it propagates through the waveguide 122. The optical waveguide mode preferably has a spatial extent that is much wider than the waveguide 122 itself, the extent depending on the refractive index of the substrate 118. In particular, the optical waveguide mode has an evanescent wave/tail that extends into the superstrate 103 (sensing region) which “sees” any surface changes created when the biological substance 124 approaches or comes in contact with the top surface 126 of the biosensor 102.
The previous expression shown in equation no. 2 may be rewritten in the more convenient form shown in equation no. 3:
which is the equation of a line where sin θ being the y axis, λ being the x-axis, Λneff the x-intercept, and −1/Λ the slope. To obtain equation no. 3, ninc has been set to 1 so that it could be removed from this expression. This approximation is used since air (n−1.0003) is the most common incident medium. This relation is pictured in the graph shown in
The resonant condition (e.g., resonant wavelength or resonant angle) of such a biosensor 102 may be interrogated to determine refractive index changes by observing the optical beam 112 reflected from the biosensor 102 (see
Referring again to
As mentioned above, the raw spectral data 114 can be analyzed by the processor 110 to enable a wide range of tasks to be performed. For instance, the raw data 114 can be used to: (1) detect biomolecular binding event(s); (2) characterize the biosensor 102; (3) register the biosensor 102; and (4) mitigate optical system artifacts. Each of these tasks is described in greater detail below with respect to
Detect Biomolecular Binding Event(s)
How the optical reader system 100 and 100′ can use a scanned optical beam 104 to interrogate one or more biosensors 104 has been described above with respect to
However such referencing techniques are imperfect, since any two biosensors 102 may see different signals due to pipetting errors, temperature gradients, or other well-to-well (sensor-to-sensor) changes. An improved strategy has been developed in which a sample (binding) region and reference (non-binding) region are formed on the same biosensor 102. How this can be done was described in detail in a related U.S. patent application Ser. No. 11/027,509 entitled “Method for Creating a Reference Region and a Sample Region on a Biosensor and the Resulting Biosensor”.
Following are descriptions about the results of several experiments that were conducted to show how one can better detect a biomolecular binding event in the presence of undesired environmental noise using the optical reader system 100′ and microplate 516 shown in
Characterization of Biosensor 102
As briefly mentioned above, the optical reader system 100 can use a scanned optical beam 104 and the resulting raw spectral data 114 to perform a variety of tasks like create a spatial map of sensor resonant wavelength, reflectivity, peak width, local angle, wavelength interrogation slope (WIS), and other parameters. Some of these spatial maps can be used to characterize a biosensor 102 and 102′. For instance, an example of a spatial map of reflectivity that was obtained from a group of biosensors 102 using small optical beams 104 (˜100 micron diameter) is shown in the graph of
Register the Biosensor 102
The optical reader system 100 can also use a scanned optical beam 104 and the resulting raw spectral data 114 to create a spatial map of reflected power that enables one to precisely locate the edge of the biosensor's gratings 120 (or similar fiducial markings). One can obtain this information by taking the derivative of the power vs. position data and then using the minimum and maximum derivative values to locate the edges of the biosensor 102 as is shown in the graph illustrated in
The results of several experiments where the edges of biosensor's gratings 120 were located from such power vs. position data are shown in the graph of
Mitigate Optical System Effects
A second problem associated with repositioning the sensor plate 102 is the angular dependence of the resonance wavelength. Although single mode fibers can be used which should, at first order, be angularly insensitive, some angular dependence can be observed which depends on the lens aberration and on the position of the beam over the grating 120. So, to minimize this error contribution, the same lens should be used for interrogating both the reference and the measurement channels. Also, by scanning the sensor length, one can average the contribution associated with the sensor non-homogeneity so that one can get very repeatable angular sensitivity curves.
Following is a description about another experiment that was performed to evaluate the capabilities of the scanned optical reader system 100. Basically, this experiment was performed to determine if there was an advantage of using small interrogating beam sizes and scanning methods to reduce the angular and lateral sensitivities of the measurements.
Two different instrument configurations were analyzed and are referred hereinafter as static configuration and dynamic configuration. In the static configuration, the reference and the measurement areas of the same biosensor 102 were sequentially interrogated by an optical reader system that did not scan the optical beam 104 across the biosensor 102. And, in the dynamic configuration, the reference and the measurement areas of the same biosensor 102 were interrogated by an optical reader system 100 that continuously scanned an optical beam 104 over grating sub-areas called “pads” on the biosensors 102. In the dynamic condition, the resonance wavelength is calculated as the average over the ‘pad’ length. The biosensors 102 in this experiment used a waveguide made from Nb2O5.
1. Angular Sensitivity in Static Conditions
1.1 Large Beam Diameter & Normal Incidence
To calculate the impact of an angular misalignment upon the measurement, one must determine dλ/dθ at the “measurement” location and at the “reference” location of a sensor. Sometimes, one may be lucky and dλ/dθ may be equal at both spatial locations but this is not guaranteed. The worst case corresponds to the case where dλ/dθ is maximum for one and minimum for the other. So, although the average dλ/dθ is close to 15 pm/mRd, the impact on the measurement accuracy might be up to 100 pm/mRd at 0 mRd incidence. Moreover, although the average curve appears to be quite repeatable from one biosensor 102 to another one, the MAX and MIN values can significantly change making the results even worse.
1.2 Small Beam Diameter & Normal Incidence
Next, a smaller beam 104 was used where “small” means much smaller than the distance over which the beam 104 is scanned. And, the following curves shown in
2.0 Angular Sensitivity in Dynamic Conditions
2.1 Small Beam Diameter & Normal Incidence
An advantage of scanning the biosensor 102 is that, by averaging the data over large areas, all variations that have spatial periods less than the scanning range can be averaged. So, the problem of the difference between dλ/dθ at the reference position and at the measurement position drastically decrease.
2.2 Large Beam Diameter & Normal Incidence
One can apply the same logic to the case of a 500 microns beam diameter. The problem with this case is that the period of the variations are of the same order of magnitude than the length of the scan so that the impact of averaging over half of the biosensor 102 does not work as well as in the previous case as can be seen in
3.0 Lateral Sensitivity in Static Conditions
One can use the same curves as above to determine the sensitivity to lateral displacement. In this case, the angle was fixed and we calculated for each angle the amplitude of dλ/dx.
4. Lateral Sensitivity in Dynamic Conditions
For angular sensitivity, the idea is that by integrating the signal over relatively large sub-areas (PADS 1 & 2) of the biosensor 102, one can then average the dλ/dθ.
In this experiment, the static configuration and the dynamic configuration were tested. And, for each of these configurations, two different beam sizes were investigated.
In reviewing, the measurement angular sensitivity data it can be concluded the scanning approach with a small beam in accordance with the present invention resulted in an impressive improvement as can be seen in TABLE #1.
Angular sensitivities (pm/mRd)
PHI = 115 microns
PHI = 500 microns
Static (worst case)
If the sensitivity to lateral translation is analyzed, then one can conclude that small beam/scanning also achieves better performance as shown in TABLE #2.
TABLE #2 Lateral sensitivities (pm/microns) PHI = 115 microns PHI = 500 microns Static (worst case) 2.4 1 Scanning 0.3 Not measured
Additional 2-Dimensional Scan Experiment
It was briefly mentioned above how the optical reader system 100 can be used to perform a 2-D scan of a biosensor 102. To prove the feasibility of this feature an experiment was performed in which the optical reader system 100′ was in a 2-D scanning mode. In this mode, a linear scan was taken across a biosensor, the microplate 516 was then stepped over by approximately one optical beam width in a direction perpendicular to the linear scan, and the linear scan was repeated, and so on.
Some additional features and advantages of using the scanned optical reader system 100 and 100′ to interrogate/characterize the biosensor 102 and 102′ are described below as follows:
It should be noted that in most of the drawings herein, were made based on the assumption that the sensor is spectrally interrogated. This means that the sensor is interrogated at a fixed incidence angle with a broad spectral source and that the wavelength is detected in the reflected beam. The source is then a broad spectral source and the detector is a wavelength sensitive detector such as a spectrometer. However, it should be appreciated that the principle of the present invention can also be extended to an angular interrogation approach where the sensor is interrogated with monochromatic light and then a resonant angle is detected in the reflected beam.
Although multiple embodiments of the present invention have been illustrated in the accompanying Drawings and described in the foregoing Detailed Description, it should be understood that the invention is not limited to the embodiments disclosed, but is capable of numerous rearrangements, modifications and substitutions without departing from the spirit of the invention as set forth and defined by the following claims.
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|Clasificación de EE.UU.||435/288.7, 385/37, 422/82.11, 359/263, 356/244, 356/300, 422/82.05, 356/328, 385/12, 436/164, 422/82.09, 356/73.1, 359/196.1|
|Clasificación internacional||G01J3/00, C12M1/34, G01N21/00, G02B6/34, G01J3/28, G02F1/07, G02B26/08, G02B6/00, G01N21/01|
|Clasificación cooperativa||G01N21/253, G01N21/554, G01N21/7743|
|Clasificación europea||G01N21/55B2N, G01N21/25B2, G01N21/77B3A|
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